CSF Alzheimer Disease Biomarkers

Abstract

Background and ObjectivesThis study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)–related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E (ApoE4) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset.MethodsMeasures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI.ResultsAnalyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age.DiscussionThe lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response.

Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment

“…Notably, in the current study, higher Aβ 40 levels were also associated with higher temporal WMH volumes among all subjects and the cognitively normal subgroup, though this association was less robust than for p-tau and t-tau. Although altered levels of Aβ 40 are not typically observed in AD, including the preclinical phase (e.g., [ 57 ]), a recent multicenter study reported slightly, but significantly higher levels of Aβ 40 among patients with AD-dementia compared to controls [ 58 ]. Within this context, it has been suggested that increased Aβ 40 may be a marker of elevated overall amyloid production [ 46, 58 ], overall CSF production [ 59 ], or of reduced clearance of peptides from the brain into the CSF [ 47 ].…”

Longitudinal CSF Alzheimer's disease biomarker changes from middle age to late adulthood

“…Samples were aliquoted into polypropylene cryotubes that were kept on dry ice and immediately transferred to a –80°C freezer for long‐term storage. Samples were thawed for the first time since collection to measure Aβ 40 , Aβ 42 , p‐tau 181 , and t‐tau using fully automated electrochemiluminescence assays (Lumipulse G1200 platform; Fujirebio Diagnostics, Inc.; for coefficients of variation, see Greenberg et al 11 …”

“…[3][4][5] Furthermore, we explored interactions with sex, because prior studies have reported sex-related differences in AD biomarkers [6][7][8] and clinical outcomes. [9][10][11][12] Finally, given the sizeable number of individuals who progressed to mild cognitive impairment (MCI) or dementia (n = 94) during followup, we examined whether CSF biomarker trajectories differed with respect to clinical outcomes. The focus on middle-aged individuals is particularly important because AD pathology begins to develop in midlife, 5,13 and abnormal midlife levels of CSF amyloid and tau are associated with poorer cognitive outcomes.…”

“…The focus on middle-aged individuals is particularly important because AD pathology begins to develop in midlife, 5,13 and abnormal midlife levels of CSF amyloid and tau are associated with poorer cognitive outcomes. 11,14,15 2 METHODS…”

“…We also examined associations among the biomarker measures, and tested the hypothesis that APOE ε4‐related differences in biomarker trajectories are due to differences in amyloid positivity between APOE ε4 carriers and non‐carriers, given APOE ε4 carriers accumulate amyloid earlier than non‐carriers 3–5 . Furthermore, we explored interactions with sex, because prior studies have reported sex‐related differences in AD biomarkers 6–8 and clinical outcomes 9–12 . Finally, given the sizeable number of individuals who progressed to mild cognitive impairment (MCI) or dementia ( n = 94) during follow‐up, we examined whether CSF biomarker trajectories differed with respect to clinical outcomes.…”